sodium channels and pain 2

Question 1

what can block the alpha subunits of VGSCs?

Answer 1

• tetrodotoxin (TTX)
• produced by bacteria in the puffer fish
• alpha subints can be TTX senstive or resistant (more TTX needed to block channel)

Question 2

what makes Nav1.8 and 1.9 better pain targets

Answer 2

as are PNS specific (will not disrupt CNS if targetted)

- also are TTX resistant so a small concentration of TTX should not be lethal

Question 3

what are the models used to analyse pain behaviour in KO mice?

Answer 3

• acute pain thresholds to mechanical and thermal stimuli - baseline
• neuropathic pain models - examine drop in acute thresholds following damage to sensory nerves
• inflammatory pain models - examine drop in acute thresholds after inflammation

Question 4

what is neuropathic pain?

Answer 4

-pain resulting in actual or potential damage to the somatosensory NS.

Question 5

why are animals good subjects to model pain?

Answer 5

• less ethical issues
• conserved gene pathways
• less subjective to pain

Question 6

how are mechanical /thermal thresholds measured?

Answer 6

• withdrawal when pain if felt - less subjective in animals

- von frey hairs - mechanical stimulus to measure thresholds

Question 7

where is Nav1.3 expressed?

Answer 7

• expressed in CNS and PNS
• embryonic expression which decreases postnatally
• very low expression in adults

Question 8

What is the contribution of Nav1.3 to pain?

Answer 8

• Nav1.3 is upregulated in chronic pain models - (is this facilitating pain? - no)
• BUT no deficit in pain when Nav1.3 is ablated in mouse in behavioural studies
• no more money/time invested

Question 9

what is Nav1.8 contribution to pain?

PNS specific

Answer 9

• expressed in specfic set of neurons which are TTx-resistant
• when Nav1.8 ablated mice become accute pressure resistant and inflammatory pain in reduced

-other studies which investigate KD approach and Nav1.8 blocker shows effects to be analgesic

Question 10

what happens in GOF Nav1.8 mutations?

Answer 10

-painful neuropathy

Question 11

what is contribution of Nav1.9 to pain?

Answer 11

Nav1.9 - TTX resistant

deletions of Nav1.9 - inflammatory pain attenuated

Question 12

What happens in GOF muations in SCN11A (Nav1.9)?

Answer 12

• pain in lower extremeties
• pain increases with fatigue
• pain relieved by oral administration of AI analgesic drugs